Hyperfibrinogenemia and sphingolipid-mediated cerebrovascular permeability and memory impairment during TBI
TBI期间高纤维蛋白原血症和鞘脂介导的脑血管通透性和记忆障碍
基本信息
- 批准号:10855710
- 负责人:
- 金额:$ 75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-15 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAlzheimer&aposs DiseaseAlzheimer&aposs disease related dementiaAlzheimer&aposs disease riskAstrocytesAttenuatedAvidityBindingBloodBlood ProteinsBlood VesselsBrainCaveolaeComplexConfocal MicroscopyCortical ContusionsCrossbreedingDataDementiaDepositionDevelopmentDiseaseElectron MicroscopyElectronsEndothelial CellsEndotheliumEnzymesExocytosisExtravasationFibrinogenFluorescenceFluorescence Resonance Energy TransferFumonisinsGenerationsGlucosylceramidesGoalsHeart DiseasesImmunohistochemistryImpaired cognitionIn SituIn VitroInflammationInjuryIntercellular adhesion molecule 1Knockout MiceMAPK3 geneMeasuresMediatingMemoryMemory LossMemory impairmentMethodsMicroscopyMitochondriaModelingMorbidity - disease rateMusN-palmitoylsphingosinePathogenicityPathway interactionsPeripheral Nervous SystemPermeabilityPhosphorylationPilot ProjectsPrPProductionProteinsResearchResearch PriorityResistanceRoleShort-Term MemorySignal TransductionSmall Interfering RNASphingolipidsSphingomyelinsTestingTracerTransgenic OrganismsTraumatic Brain InjuryUnited States National Institutes of HealthVascular Cognitive ImpairmentVascular DiseasesVascular Endothelial Cellblood-brain barrier permeabilizationbrain endothelial cellcaveolin 1cerebrovasculardihydroceramide desaturasein vivoinhibitorinsightknockout geneloss of functionmortalitymouse modelneuroinflammationnew therapeutic targetnovelobject recognitionprotein complexreceptorserine palmitoyltransferasethermozymocidintranscytosis
项目摘要
Project Summary
Increased blood content of fibrinogen (Fg), e.g. hyperfibrinogenemia (HFg) is a risk factor for Alzheimer's disease
(AD). As it occurs during neuroinflammation, it is a risk factor for AD & related disorders (ADRD), including
vascular cognitive impairment & dementia (VCID). Our goal is to characterize the role of a novel mechanistic
pathway, namely Fg-sphingolipid-caveolae nexus during traumatic brain injury (TBI) as an example of ADRD,
which is accompanied with HFg. Our data indicate that cortical contusion injury (CCI)-induced HFg enhances
cerebrovascular permeability mainly via caveolar protein transcytosis leading to Fg deposition in extravascular
space and resulting in greater formation of Fg and cellular prion protein complexes resulting in short-term memory
(STM) reduction, typically occurring in AD. We showed that HFg increased Fg binding to endothelial intercellular
adhesion molecule-1 (ICAM-1) enhancing formation of functional caveolae & exocytosis via activation of ERK-1/2
and caveolin-1 (Cav-1). We found that HFg upregulated de novo sphingolipid synthesis pathway & caveolar
transcytosis using mitochondrial ATP. A selective inhibitor of sphingolipid synthesis pathway ameliorated the HFg-
triggered caveolar protein transcytosis in mouse brain endothelial cells, & importantly, reduced cerebrovascular
protein transcytosis after CCI. Based on these results, we hypothesize that at elevated levels, Fg, through binding
to its endothelial receptor ICAM-1, activates sphingolipid production resulting in increased caveolar protein
transcytosis in ECs that is supported by ATP generated in mitochondria. A corollary hypothesis is that an enhanced
caveolar Fg transcytosis contributes to STM reduction similar to that during AD. Specific aims are: (1) Determine
whether the increased interaction of Fg with endothelial ICAM-1 enhances formation of functional caveolae via
production of Cer, GlcCer, and SPM sphingolipids and thereby increases caveolae-mediated protein transcytosis.
(2) Determine whether increased interaction of Fg with ECs enhances mitochondrial activity using up energy for
caveolar protein transcytosis. (3) Determine whether inhibition of de novo sphingolipid synthesis attenuates HFg-
induced increased formation of functional caveolae decreasing caveolar protein transcytosis and thus, ameliorates
the STM reduction during TBI. To test mechanisms of HFg-induced caveolar transcytosis via sphingolipid
signaling we will use WT, HFg, and endothelium-specific serine palmitoyltransferase long chain-2 gene knockout
(Sptlc2endo-/-) and HFg/Sptlc2endo-/- mice generated by Cre/lox method, with or without CCI. The dual-tracer probing
method will be used to define changes in caveolar transcytosis. Loss-of-function strategy (specific siRNAs against
ICAM-1 & Cav-1) and specific inhibitors of sphingolipid synthesis will be used. Immunohistochemistry and intravital,
confocal, electron, total internal reflection fluorescence, and fluorescence resonance energy transfer microscopies
will be used. Changes in STM will be assessed by a novel object recognition and Y-maze tests. These studies will
provide insight into the role of sphingolipids in mechanisms of cerebrovascular permeability & may unveil new
therapeutic targets for one of the leading causes of VCID.
项目摘要
血液中纤维蛋白原(Fg)含量增加,例如高纤维蛋白原血症(HFg)是阿尔茨海默病的危险因素
(AD)。由于它发生在神经炎症期间,它是AD及相关疾病(ADRD)的风险因素,包括
血管性认知障碍和痴呆(VCID)。我们的目标是描述一种新的机械
途径,即创伤性脑损伤(TBI)期间的Fg-鞘脂-小窝关系,作为ADRD的一个例子,
它伴随着HFg。我们的数据表明,皮质挫伤(CCI)诱导的HFg增强
脑血管通透性主要通过小窝蛋白转胞吞作用导致血管外Fg沉积
空间,并导致更多的Fg和细胞朊病毒蛋白复合物的形成,从而导致短期记忆
(STM)减少,通常发生在AD。我们发现HFg增加了Fg与内皮细胞间的结合,
粘附分子-1(ICAM-1)通过激活ERK-1/2促进功能性小窝和胞吐作用的形成
和Caveolin-1(Cav-1)。我们发现HFg上调了鞘脂的从头合成途径&小窝
使用线粒体ATP进行胞吞转运。鞘脂合成途径的选择性抑制剂改善了HFg-
触发小鼠脑内皮细胞中的小窝蛋白转胞吞作用,重要的是,
CCI后的蛋白质转胞吞作用。基于这些结果,我们假设在升高的水平下,Fg通过结合
与其内皮受体ICAM-1结合,激活鞘脂产生,导致小窝蛋白增加
在EC中的转胞吞作用由线粒体中产生的ATP支持。一个必然的假设是,
小窝Fg转胞吞作用有助于STM减少,类似于AD期间。具体目标是:(1)确定
Fg与内皮细胞ICAM-1相互作用的增加是否通过
Cer、GlcCer和SPM鞘脂的产生,从而增加小窝介导的蛋白质转胞吞作用。
(2)确定增加的Fg与EC的相互作用是否增强线粒体活性,
小窝蛋白转胞吞作用(3)确定从头鞘脂合成的抑制是否减弱HFg-
诱导功能性小窝形成增加,减少小窝蛋白转胞吞作用,从而改善
TBI期间STM减少。检测HFg通过鞘脂诱导小窝转胞吞的机制
我们将使用WT、HFg和内皮特异性丝氨酸棕榈酰转移酶长链-2基因敲除
(Sptlc 2 endo-/-)和HFg/Sptlc 2 endo-/-小鼠。双示踪剂探测
方法将用于定义小窝转胞吞的变化。功能丧失策略(针对
ICAM-1和Cav-1)和鞘脂合成的特异性抑制剂。免疫组织化学和活体,
共聚焦、电子、全内反射荧光和荧光共振能量转移显微术
将用于STM的变化将通过新的物体识别和Y-迷宫测试来评估。这些研究将
提供对鞘脂在脑血管通透性机制中的作用的深入了解,并可能揭示新的
VCID主要病因之一的治疗靶点。
项目成果
期刊论文数量(0)
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{{ truncateString('DAVID LOMINADZE', 18)}}的其他基金
Mechanisms of neurodegeneration by a fibrinogen-containing protein complex during traumatic brain injury
创伤性脑损伤期间含纤维蛋白原的蛋白质复合物引起神经退行性变的机制
- 批准号:
10161854 - 财政年份:2019
- 资助金额:
$ 75万 - 项目类别:
Mechanisms of neurodegeneration by a fibrinogen-containing protein complex during traumatic brain injury
创伤性脑损伤期间含纤维蛋白原的蛋白质复合物引起神经退行性变的机制
- 批准号:
10402868 - 财政年份:2019
- 资助金额:
$ 75万 - 项目类别:
Mechanisms of neurodegeneration by a fibrinogen-containing protein complex during traumatic brain injury
创伤性脑损伤期间含纤维蛋白原的蛋白质复合物引起神经退行性变的机制
- 批准号:
10027325 - 财政年份:2019
- 资助金额:
$ 75万 - 项目类别:
Mechanisms of Homocysteine-Induced Fibrinogen-Amyloid Plaque Formation
同型半胱氨酸诱导纤维蛋白原淀粉样蛋白斑形成的机制
- 批准号:
8689198 - 财政年份:2013
- 资助金额:
$ 75万 - 项目类别:
Mechanisms of Homocysteine-Induced Fibrinogen-Amyloid Plaque Formation
同型半胱氨酸诱导纤维蛋白原淀粉样蛋白斑形成的机制
- 批准号:
8599053 - 财政年份:2013
- 资助金额:
$ 75万 - 项目类别:
Fibronogen-Induced Vasconstriction during Hypertension
高血压期间纤维蛋白原诱导的血管收缩
- 批准号:
7838826 - 财政年份:2009
- 资助金额:
$ 75万 - 项目类别:
Fibrinogen-induced vasoconstriction during hypertension
高血压期间纤维蛋白原诱导的血管收缩
- 批准号:
7209670 - 财政年份:2007
- 资助金额:
$ 75万 - 项目类别:
Fibrinogen-Induced Vasoconstriction during Hypertension
高血压期间纤维蛋白原诱导的血管收缩
- 批准号:
7788167 - 财政年份:2007
- 资助金额:
$ 75万 - 项目类别:
Fibrinogen-induced vasoconstriction during hypertension
高血压期间纤维蛋白原诱导的血管收缩
- 批准号:
7360319 - 财政年份:2007
- 资助金额:
$ 75万 - 项目类别:
Fibrinogen-Induced Vasoconstriction during Hypertension
高血压期间纤维蛋白原诱导的血管收缩
- 批准号:
7575795 - 财政年份:2007
- 资助金额:
$ 75万 - 项目类别: